Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof

ABSTRACT

The application relates to a compound of Formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, which modulates the activity of BTK, a pharmaceutical composition comprising the compound of Formula (I), and a method of treating or preventing a disease in which BTK plays a role.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/757,745, filed Dec. 23, 2015 (now allowed), the entire contents ofwhich are incorporated herein by reference.

FIELD OF THE APPLICATION

The present application is directed to inhibitors of Bruton's TyrosineKinase (BTK), including mutant BTK, useful in the treatment of diseasesor disorders associated with BTK kinase, including immune disorders,cancer, cardiovascular diseases, viral infections, inflammation,metabolism/endocrine function disorders, and neurological disorders.Specifically, the application is concerned with compounds andcompositions thereof, which inhibit BTK, methods of treating diseases ordisorders associated with BTK and methods of synthesis of thesecompounds.

BACKGROUND

BTK is a member of the Tec family of tyrosine kinases and plays animportant role in the regulation of early B-cell development and matureB-cell activation and survival. (Hunter, Cell, 1987 50, 823-829).Functioning downstream of multiple receptors, such as growth factors,B-cell antigen, chemokine, and innate immune receptors, BTK initiates anumber of cellular processes including cell proliferation, survival,differentiation, motility, angiogenesis, cytokine production, andantigen presentation.

BTK-deficient mouse models have shown the role BTK plays in allergicdisorders and/or autoimmune disease and/or inflammatory disease. Forinstance, BTK deficiency in standard murine preclinical models ofsystemic lupus erythematosus (SLE) has been shown to result in a markedamelioration of disease progression. Furthermore, BTK-deficient mice canbe resistant to developing collagen-induced arthritis and lesssusceptible to Staphylococcus-induced arthritis. Due to BTK's role inB-cell activation, BTK inhibitors can also be useful as inhibitors ofB-cell mediated pathogenic activity (such as autoantibody production).Expression of BTK in osteoclasts, mast cells and monocytes has beenshown to be important for the function of these cells. For example,impaired IgE-mediated mast cell activation and reduced TNF-alphaproduction by activated monocytes has been associated with BTKdeficiency in mice and humans. Thus, BTK inhibition can be useful forthe treatment of allergic disorders and/or autoimmune and/orinflammatory diseases such as: SLE, rheumatoid arthritis, multiplevasculitides, idiopathic thrombocytopenic purpura (ITP), myastheniagravis, allergic rhinitis, and asthma (DiPaolo et. al., Nature Chem.Biol. 2011, 7(1):41-50; Liu et. al., Jour. Pharmacol. and Exp. Ther.2011, 338(1): 154-163).

Moreover, BTK's role in apoptosis demonstrates the utility of inhibitionof BTK activity for the treatment of cancers, B-cell lymphoma, leukemia,and other hematological malignancies. In addition, given the role of BTKin osteoclast function, inhibition of BTK activity can be useful for thetreatment of bone disorders such as osteoporosis.

Inhibition of BTK with small molecule inhibitors therefore has thepotential to be a treatment for immune disorders, cancer, cardiovasculardiseases, viral infections, inflammation, metabolism/endocrine functiondisorders, and neurological disorders. Thus, there remains aconsiderable need for potent small molecule inhibitors of BTK.

SUMMARY

A first aspect of the application relates to a compound of Formula (I):

or pharmaceutically acceptable salts thereof, tautomers, prodrugs,solvates, metabolites, polymorphs, analogs or derivatives thereof. Asused herein, the expressions “compound of Formula (I)” and “Compound(I),” refer to the same compound and can be used interchangeably.

Another aspect of the application relates to a pharmaceuticalcomposition comprising the compound of Formula (I) or a pharmaceuticallyacceptable salt, tautomer, prodrug, solvate, metabolite, polymorph,analog or derivative thereof, and a pharmaceutically acceptable diluent,excipient or carrier.

Another aspect of the application relates to a method of treating aBTK-mediated disorder. The method comprises administering to a patientin need of a treatment for diseases or disorders associated withmodulation of BTK kinase a therapeutically effective amount of thecompound of Formula (I), or a pharmaceutically acceptable salt,tautomer, prodrug, solvate, metabolite, polymorph, analog or derivativethereof.

Another aspect of the application relates to a method of treating aBTK-mediated disorder. The method comprises administering to a patientin need of a treatment for diseases or disorders associated withmodulation of BTK kinase a therapeutically effective amount of apharmaceutical composition comprising the compound of Formula (I) or apharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof, and apharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the application relates to a method of treating a cellproliferative disorder. The method comprises administering to a patientin need thereof a therapeutically effective amount of the compound ofFormula (I), or a pharmaceutically acceptable salt, tautomer, prodrug,solvate, metabolite, polymorph, analog or derivative thereof.

Another aspect of the application relates to a method of treating a cellproliferative disorder. The method comprises administering to a patientin need thereof a therapeutically effective amount of a pharmaceuticalcomposition comprising the compound of Formula (I) or a pharmaceuticallyacceptable salt, tautomer, prodrug, solvate, metabolite, polymorph,analog or derivative thereof, and a pharmaceutically acceptable diluent,excipient or carrier.

Another aspect of the application relates to a method of treatingcancer. The method comprises administering to a patient in need thereofa therapeutically effective amount of the compound of Formula (I), or apharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof.

Another aspect of the application relates to a method of treatingcancer. The method comprises administering to a patient in need thereofa therapeutically effective amount of a pharmaceutical compositioncomprising the compound of Formula (I) or a pharmaceutically acceptablesalt, tautomer, prodrug, solvate, metabolite, polymorph, analog orderivative thereof, and a pharmaceutically acceptable diluent, excipientor carrier.

Another aspect of the application relates to a method of modulating(e.g., inhibiting) BTK. The method comprises administering to a patientin need thereof a therapeutically effective amount of the compound ofFormula (I), or a pharmaceutically acceptable salt, tautomer, prodrug,solvate, metabolite, polymorph, analog or derivative thereof.

Another aspect of the application relates to a method of modulating(e.g., inhibiting) BTK. The method comprises administering to a patientin need thereof a therapeutically effective amount of a pharmaceuticalcomposition comprising the compound of Formula (I) or a pharmaceuticallyacceptable salt, tautomer, prodrug, solvate, metabolite, polymorph,analog or derivative thereof, and a pharmaceutically acceptable diluent,excipient or carrier.

Another aspect of the application relates to the compound of Formula (I)or a pharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof, for use in a methodof treating a BTK-mediated disorder, a cell proliferative disorder, orcancer, or of modulating (e.g., inhibiting) BTK. The compound of Formula(I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof is administered in atherapeutically effective amount to a patient in need thereof.

Another aspect of the application relates to a pharmaceuticalcomposition comprising the compound of Formula (I) or a pharmaceuticallyacceptable salt, tautomer, prodrug, solvate, metabolite, polymorph,analog or derivative thereof, and a pharmaceutically acceptable diluent,excipient or carrier for use in a method of treating a BTK-mediateddisorder, a cell proliferative disorder, or cancer, or of modulating(e.g., inhibiting) BTK. The composition is administered in atherapeutically effective amount to a patient in need thereof.

Another aspect of the application relates to the use of the compound ofFormula (I) or a pharmaceutically acceptable salt, tautomer, prodrug,solvate, metabolite, polymorph, analog or derivative thereof, in themanufacture of a medicament for treating a BTK-mediated disorder, a cellproliferative disorder, or cancer, or for modulating (e.g., inhibiting)BTK. The compound of Formula (I), or a pharmaceutically acceptable salt,tautomer, prodrug, solvate, metabolite, polymorph, analog or derivativethereof is administered in a therapeutically effective amount to apatient in need thereof.

Another aspect of the application relates to the use of a pharmaceuticalcomposition comprising the compound of Formula (I) or a pharmaceuticallyacceptable salt, tautomer, prodrug, solvate, metabolite, polymorph,analog or derivative thereof, and a pharmaceutically acceptable diluent,excipient or carrier in the manufacture of a medicament for treating aBTK-mediated disorder, a cell proliferative disorder, or cancer, or formodulating (e.g., inhibiting) BTK. The composition is administered in atherapeutically effective amount to a patient in need thereof.

The present application further provides methods of treating a diseaseor disorder associated with modulation of BTK kinase including, but notlimited to, immune disorders, cancer, cardiovascular diseases, viralinfections, inflammation, metabolism/endocrine function disorders, andneurological disorders comprising, administering to a patient sufferingfrom at least one of said diseases or disorders the compound of Formula(I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof.

The present application provides inhibitors of BTK that are therapeuticagents in the treatment of diseases such as immune disorders, cancer,cardiovascular diseases, viral infections, inflammation,metabolism/endocrine function disorders, neurological disorders andother disease associated with the modulation of BTK kinase.

The present application further provides compounds and compositions withan improved efficacy and safety profile relative to known BTKinhibitors. The present application also provides agents with novelmechanisms of action toward BTK kinase in the treatment of various typesof diseases including immune disorders, cancer, cardiovascular diseases,viral infections, inflammation, metabolism/endocrine function disorders,and neurological disorders. Ultimately the present application providesthe medical community with a novel pharmacological strategy for thetreatment of diseases and disorders associated with BTK kinase.

DETAILED DESCRIPTION

The present application relates to a compound and compositions that arecapable of modulating the activity Bruton's Tyrosine Kinase (BTK). Theapplication features methods of treating, preventing or ameliorating adisease or disorder in which BTK plays a role by administering to apatient in need thereof a therapeutically effective amount of thecompound of Formula (I), or a pharmaceutically acceptable salt,tautomer, prodrug, solvate, metabolite, polymorph, analog or derivativethereof. The methods of the present application can be used in thetreatment of a variety of BTK-mediated diseases and disorders byinhibiting the activity of BTK kinase. Inhibition of BTK providestreatment, prevention, or amelioration of diseases including, but notlimited to, immune disorders, cancer, cardiovascular diseases, viralinfections, inflammation, metabolism/endocrine function disorders andneurological disorders.

In a first aspect of the application, the compound of Formula (I) isdescribed:

and pharmaceutically acceptable salts thereof, tautomers, prodrugs,solvates, metabolites, polymorphs, analogs or derivatives thereof.

In one embodiment, the compound of Formula (I) is a pharmaceuticallyacceptable salt. In another embodiment, the compound of Formula (I) is ahydrate. In yet another embodiment, the compound of Formula (I) is asolvate.

The details of the application are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent application, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the applicationwill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this application belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

Definitions

The articles “a” and “an” are used in this application to refer to oneor more than one (i.e., at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this application to mean either “and” or“or” unless indicated otherwise.

The application also includes pharmaceutical compositions comprising aneffective amount of the compound of Formula (I) and a pharmaceuticallyacceptable carrier.

The term “carrier”, as used in this application, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The compound of Formula (I) may form salts which are also within thescope of this application. Reference to a compound of the Formula hereinis understood to include reference to salts thereof, unless otherwiseindicated.

Representative “pharmaceutically acceptable salts” include, e.g.,water-soluble and water-insoluble salts, such as the acetate, amsonate(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate,bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium,calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate,dihydrochloride, edetate, edisylate, estolate, esylate, fumerate,fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts.

The compounds of the present application, for example, including thepharmaceutically acceptable salts, tautomers, prodrugs, and polymorphsof the compounds, can exist in a solvated form with other solventmolecules or in an unsolvated form.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundsor salts have a tendency to trap a fixed molar ratio of solventmolecules in the crystalline solid state, thus forming a solvate. If thesolvent is water the solvate formed is a hydrate; and if the solvent isalcohol, the solvate formed is an alcoholate. Hydrates are formed by thecombination of one or more molecules of water with one molecule of thesubstance in which the water retains its molecular state as H₂O.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this application, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). For example, ifa compound of Formula (I) incorporates a double bond or a fused ring,both the cis-and trans-forms, as well as mixtures, are embraced withinthe scope of the application. Individual stereoisomers of the compoundof the application may, for example, be substantially free of otherisomers, or may be admixed, for example, as racemates or with all other,or other selected, stereoisomers. The chiral centers of the presentapplication can have the S or R configuration as defined by the IUPAC1974 Recommendations. The use of the terms “salt”, “solvate”, “ester,”“prodrug” and the like, is intended to equally apply to the salt,solvate, ester and prodrug of enantiomers, stereoisomers, rotamers,tautomers, positional isomers, racemates or prodrugs of the inventivecompounds.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesor as individual enantiomers or diastereomers.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent application includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like.

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

The compounds of the application may contain asymmetric or chiralcenters, and, therefore, exist in different stereoisomeric forms. It isintended that all stereoisomeric forms of the compounds of theapplication as well as mixtures thereof, including racemic mixtures,form part of the present application. In addition, the presentapplication embraces all geometric and positional isomers. For example,if a compound of the application incorporates a double bond or a fusedring, both the cis-and trans-forms, as well as mixtures, are embracedwithin the scope of the application. Each compound herein disclosedincludes all the enantiomers that conform to the general structure ofthe compound. The compound may be in a racemic or enantiomerically pureform, or any other form in terms of stereochemistry. The assay resultsmay reflect the data collected for the racemic form, theenantiomerically pure form, or any other form in terms ofstereochemistry.

A carbon atom bonded to four non-identical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

In another embodiment of the application, the compound of Formula (I) isan enantiomer. In some embodiments the compound is the (S)-enantiomer.In other embodiments the compound is the (R)-enantiomer. In yet otherembodiments, the compounds of Formula (I) may be (+) or (−) enantiomers.The compound may contain more than one stereocenter.

In another embodiment of the application, the compounds of Formula (I)are diastereomers. In some embodiments, the compounds are the syndiastereomer. In other embodiments, the compounds are the antidiastereomer.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the application may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the application. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the application.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim,amide-imidic acid tautomerism in heterocyclic rings (e.g., innucleobases such as guanine, thymine and cytosine), amine-enamine andenamine-imine. (Pyrrolopyrimidinyl)methanone-(Pyrrolopyrimidinyl)methanol tautomeric pairs are included in the present application:

The present application relates to the compound of Formula (I) orpharmaceutically acceptable salts thereof, tautomers, prodrugs,solvates, metabolites, polymorphs, analogs or derivatives thereof,capable of inhibiting BTK, which are useful for the treatment ofdiseases and disorders associated with modulation of a BTK kinase. Theapplication further relates to the compound of Formula (I), orpharmaceutically acceptable salts thereof, tautomers, prodrugs,solvates, metabolites, polymorphs, analogs or derivatives thereof, whichare useful for inhibiting BTK. In some embodiments, the BTK is wild-typeBTK. In other embodiments, the BTK is a mutant BTK.

Another aspect of the application relates to a compound of Formula (I),wherein the compound inhibits kinase activity of a mutant BTK, such as adrug-resistant mutant BTK harboring a drug-resistance mutation (e.g.,C481S mutation). In some embodiments, the patient or subject does notrespond to a BTK inhibitor or replapse after the treatmentof a BTKinhibitor, due to a mutation of BTK kinase (e.g., a C481S mutation) thatprevents target inhibition. In one embodiment, the BTK mutation is aC481S mutation.

In some embodiments, the application provides a compound of Formula (I),wherein the compound is more potent than one or more known BTKinhibitors, including, but not limited to Ibrutinib, GDC-0834, RN486,CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and LFM-A13, atinhibiting the activity of BTK. For example, the compound can be atleast about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about100-fold more potent (e.g., as measured by IC₅₀) than Ibrutinib,GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774,and/or LFM-A13 at inhibiting the activity of the BTK.

In some embodiments, the application provides a compound of Formula (I),wherein the compound is more potent than one or more known BTKinhibitors, including, but not limited to Ibrutinib, GDC-0834, RN486,CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and LFM-A13, atinhibiting the activity of BTK containing one or more mutations asdescribed herein, e.g., C481S. For example, the compound can be at leastabout 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about100-fold more potent (e.g., as measured by IC₅₀) than Ibrutinib,GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774,and/or LFM-A13 at inhibiting the activity of the BTK containing one ormore mutations as described herein. A drug-resistant BTK mutant can havewithout limitation a drug resistance mutation comprising C481S mutation.

Potency of the inhibitor can be determined by IC₅₀ value. A compoundwith a lower IC₅₀ value, as determined under substantially similarconditions, is a more potent inhibitor relative to a compound with ahigher IC₅₀ value.

The compounds of the present application can be converted to N-oxides bytreatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid(m-CPBA) and/or hydrogen peroxides) to afford other compounds of thepresent application. Thus, all shown and claimed nitrogen-containingcompounds are considered, when allowed by valency and structure, toinclude both the compound as shown and its N-oxide derivative (which canbe designated as N→O or N⁺—O⁻). Furthermore, in other instances, thenitrogens in the compounds of the present application can be convertedto N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds canbe prepared by oxidation of the parent amine by an oxidizing agent suchas m-CPBA. All shown and claimed nitrogen-containing compounds are alsoconsidered, when allowed by valency and structure, to cover both thecompounds as shown and its N-hydroxy (i.e., N—OH) and N-alkoxy (i.e.,N—OR, wherein R is substituted or unsubstituted C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, 3-14-membered carbocycle or 3-14-memberedheterocycle) derivatives.

The term “prodrug,” as used in this application, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of Formula (I), or pharmaceutically acceptable salts,tautomers, solvates, metabolites, polymorphs, analogs or derivativesthereof can be delivered in prodrug form. Thus, the present applicationis intended to cover prodrugs of the compound of Formula (I), or apharmaceutically acceptable salt, tautomer, solvate, metabolite,polymorph, analog or derivative thereof, methods of delivering the sameand compositions containing the same. “Prodrugs” are intended to includeany covalently bonded carriers that release an active parent drug of thepresent application in vivo when such prodrug is administered to amammalian subject. Prodrugs are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of the application wherein ahydroxyl or amino, group is bonded to any group that, when the prodrugof the present application is administered to a mammalian subject, itcleaves to form a free hydroxyl or free amino group, respectively.Examples of prodrugs include, but are not limited to, acetate, formate,and benzoate derivatives of alcohol and amine functional groups in thecompounds of each of the formulae described herein or a pharmaceuticallyacceptable salt, tautomer, prodrug, solvate, metabolite, polymorph,analog or derivative thereof.

The term “crystal polymorphs”, “polymorphs” or “crystal forms” meanscrystal structures in which a compound (or a salt or solvate thereof)can crystallize in different crystal packing arrangements, all of whichhave the same elemental composition. Different crystal forms usuallyhave different X-ray diffraction patterns, infrared spectral, meltingpoints, density hardness, crystal shape, optical and electricalproperties, stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Crystal polymorphs of the compounds can beprepared by crystallization under different conditions.

As used herein, the term “analog” refers to a compound that isstructurally similar to another compound but differs slightly incomposition (as in the replacement of one atom by an atom of a differentelement or in the presence of a particular functional group, or thereplacement of one functional group by another functional group). Thus,an analog is a compound that is similar or comparable in function andappearance, but not in structure or origin to the reference compound.

The application also comprehends isotopically-labeled compounds, whichare identical to those recited in the each of the formulae describedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number most commonly found in nature. Examples of isotopes that canbe incorporated into compounds of the application include isotopes ofhydrogen, carbon, nitrogen, fluorine, such as ³H, ¹¹C, ¹⁴C, ²H, and ¹⁸F.

The compound of Formula (I), or pharmaceutically acceptable salts,tautomers, prodrugs, solvates, metabolites, polymorphs, analogs orderivatives thereof, that contains the aforementioned isotopes and/orother isotopes of other atoms are within the scope of the presentapplication. Isotopically-labeled compounds of the present application,for example those into which radioactive isotopes such as ³H, ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areuseful for their ease of preparation and detectability. ¹¹C and ¹⁸Fisotopes are useful in PET (positron emission tomography). PET is usefulin brain imaging. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances, isotopically labeled compounds of Formula (I), orpharmaceutically acceptable salts, tautomers, prodrugs, solvates,metabolites, polymorphs, analogs or derivatives thereof, can generallybe prepared by carrying out the procedures disclosed in the Schemesand/or in the Examples described herein, by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent. In one embodiment, the compound of Formula (I) orpharmaceutically acceptable salts, tautomers, prodrugs, solvates,metabolites, polymorphs, analogs or derivatives thereof, are notisotopically labelled.

The present application relates to a compound which is a modulator ofBTK. In one embodiment, the compound of the present application is aninhibitor of BTK.

The term “administer”, “administering”, or “administration” as used inthis application refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug, derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or a composition to the subject, which can form an equivalentamount of active compound within the subject's body.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” or “therapeutically effective amount” when used inconnection with a compound or pharmaceutical composition is an amounteffective for treating or preventing a disease in a subject as describedherein.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The compounds of the present application, or a pharmaceuticallyacceptable salt, tautomer, prodrug, solvate, metabolite, polymorph,analog or derivative thereof, can also be used to prevent a disease,condition or disorder. As used herein, “preventing” or “prevent”describes reducing or eliminating the onset of the symptoms orcomplications of the disease, condition or disorder.

The term “disorder” is used in this application to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

As used herein, the term “BTK-mediated” diseases or disorders means anydisease or other deleterious condition in which BTK, or a mutantthereof, is known to play a role. Accordingly, another embodiment of thepresent application relates to treating or lessening the severity of oneor more diseases in which BTK, or a mutant thereof, is known to play arole. Specifically, the present application relates to a method oftreating or lessening the severity of a disease or condition selectedfrom a proliferative disorder or an autoimmune disorder, wherein saidmethod comprises administering to a patient in need thereof a compoundsof Formula (I), or pharmaceutically acceptable salts, tautomers,prodrugs, solvates, metabolites, polymorphs, analogs or derivativesthereof, or a composition according to the present application.

As used herein, the term “cell proliferative disorder” refers toconditions in which unregulated or abnormal growth, or both, of cellscan lead to the development of an unwanted condition or disease, whichmay or may not be cancerous. Exemplary cell proliferative disorders ofthe application encompass a variety of conditions wherein cell divisionis deregulated. Exemplary cell proliferative disorder include, but arenot limited to, neoplasms, benign tumors, malignant tumors,pre-cancerous conditions, in situ tumors, encapsulated tumors,metastatic tumors, liquid tumors, solid tumors, immunological tumors,hematological tumors, cancers, carcinomas, leukemias, lymphomas,sarcomas, and rapidly dividing cells. The term “rapidly dividing cell”as used herein is defined as any cell that divides at a rate thatexceeds or is greater than what is expected or observed amongneighboring or juxtaposed cells within the same tissue. A cellproliferative disorder includes a precancer or a precancerous condition.A cell proliferative disorder includes cancer. Preferably, the methodsprovided herein are used to treat or alleviate a symptom of cancer. Theterm “cancer” includes solid tumors, as well as, hematologic tumorsand/or malignancies. A “precancer cell” or “precancerous cell” is a cellmanifesting a cell proliferative disorder that is a precancer or aprecancerous condition. A “cancer cell” or “cancerous cell” is a cellmanifesting a cell proliferative disorder that is a cancer. Anyreproducible means of measurement may be used to identify cancer cellsor precancerous cells. Cancer cells or precancerous cells can beidentified by histological typing or grading of a tissue sample (e.g., abiopsy sample). Cancer cells or precancerous cells can be identifiedthrough the use of appropriate molecular markers.

Exemplary non-cancerous conditions or disorders include, but are notlimited to, rheumatoid arthritis; inflammation; autoimmune disease;lymphoproliferative conditions; acromegaly; rheumatoid spondylitis;osteoarthritis; gout, other arthritic conditions; sepsis; septic shock;endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma;adult respiratory distress syndrome; chronic obstructive pulmonarydisease; chronic pulmonary inflammation; inflammatory bowel disease;Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreaticfibrosis; hepatic fibrosis; acute and chronic renal disease; irritablebowel syndrome; pyresis; restenosis; cerebral malaria; stroke andischemic injury; neural trauma; Alzheimer's disease; Huntington'sdisease; Parkinson's disease; acute and chronic pain; allergic rhinitis;allergic conjunctivitis; chronic heart failure; acute coronary syndrome;cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter'ssyndrome; acute synovitis; muscle degeneration, bursitis; tendonitis;tenosynovitis; herniated, ruptures, or prolapsed intervertebral disksyndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonarysarcosis; bone resorption diseases, such as osteoporosis;graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia;AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I orII, influenza virus and cytomegalovirus; and diabetes mellitus.

Exemplary cancers include, but are not limited to, adrenocorticalcarcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer,anorectal cancer, cancer of the anal canal, appendix cancer, childhoodcerebellar astrocytoma, childhood cerebral astrocytoma, basal cellcarcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bileduct cancer, intrahepatic bile duct cancer, bladder cancer, urinarybladder cancer, bone and joint cancer, osteosarcoma and malignantfibrous histiocytoma, brain cancer, brain tumor, brain stem glioma,cerebellar astrocytoma, cerebral astrocytoma/malignant glioma,ependymoma, medulloblastoma, supratentorial primitive neuroectodermaltumors, visual pathway and hypothalamic glioma, breast cancer, bronchialadenomas/carcinoids, carcinoid tumor, gastrointestinal, nervous systemcancer, nervous system lymphoma, central nervous system cancer, centralnervous system lymphoma, cervical cancer, childhood cancers, chroniclymphocytic leukemia, chronic myelogenous leukemia, chronicmyeloproliferative disorders, colon cancer, colorectal cancer, cutaneousT-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Seziary Syndrome,endometrial cancer, esophageal cancer, extracranial germ cell tumor,extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer,intraocular melanoma, retinoblastoma, gallbladder cancer, gastric(stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor (GIST), germ cell tumor, ovarian germ cell tumor,gestational trophoblastic tumor glioma, head and neck cancer,hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, ocular cancer, islet cell tumors (endocrinepancreas), Kaposi Sarcoma, kidney cancer, renal cancer, kidney cancer,laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, lip and oral cavity cancer, liver cancer, lung cancer,non-small cell lung cancer, small cell lung cancer, AIDS-relatedlymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma,Waldenstram macroglobulinemia, medulloblastoma, melanoma, intraocular(eye) melanoma, merkel cell carcinoma, mesothelioma malignant,mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer ofthe tongue, multiple endocrine neoplasia syndrome, mycosis fungoides,myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases,chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma,chronic myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer,ovarian cancer, ovarian epithelial cancer, ovarian low malignantpotential tumor, pancreatic cancer, islet cell pancreatic cancer,paranasal sinus and nasal cavity cancer, parathyroid cancer, penilecancer, pharyngeal cancer, pheochromocytoma, pineoblastoma andsupratentorial primitive neuroectodermal tumors, pituitary tumor, plasmacell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostatecancer, rectal cancer, renal pelvis and ureter, transitional cellcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, ewingfamily of sarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterinecancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer(melanoma), merkel cell skin carcinoma, small intestine cancer, softtissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, testicular cancer,throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer,transitional cell cancer of the renal pelvis and ureter and otherurinary organs, gestational trophoblastic tumor, urethral cancer,endometrial uterine cancer, uterine sarcoma, uterine corpus cancer,vaginal cancer, vulvar cancer, and Wilm's Tumor.

Method for Preparing the Compounds

The compounds of the present application may be made by a variety ofmethods, including standard chemistry. A suitable synthetic route isdepicted in the Schemes given below.

The compound of Formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the scheme described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of the compounds ofthe present application.

Those skilled in the art will recognize if a stereocenter exists in thecompound of Formula (I). Accordingly, the present application includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compound but the individual enantiomers and/ordiastereomers as well. When a compound is desired as a single enantiomeror diastereomer, it may be obtained by stereospecific synthesis or byresolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be affected by any suitable method known in the art. See, forexample, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

The compounds of the present application can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, the compounds of the present application can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. The compounds of thepresent application (i.e., the compound of Formula (I)) can besynthesized by following the steps outlined in General Scheme 1 whichcomprises a sequence of assembling intermediates 2-a to 2-h. Startingmaterials are either commercially available or made by known proceduresin the reported literature or as illustrated.

The general way of preparing the compound of Formula (I) by usingintermediates 2-a, 2-b, 2-c, 2-d, 2-e, 2-f, 2-g, and 2-h is outlined inGeneral Scheme 1. Nucleophilic addition of phenol 2-b to2-chloro-4-fluorobenzonitrile 2-a using a strong base, e.g., sodiumhydride (NaH), in a solvent, e.g., N,N-dimethylformamide (DMF), yields2-c. Hydrolysis of 2-c using a base, e.g., potassium hydroxide (KOH), ina solvent, e.g., ethanol, at an elevated temperature yields carboxylicacid 2-d. Esterification of 2-d with methyl iodide using a base, e.g.,potassium carbonate (K₂CO₃) or cesium carbonate (Cs₂CO₃), in a solvent,e.g., N,N-dimethylformamide (DMF), provides 2-e. Acylation ofintermediate 2-f with 2-e using a strong base, e.g., n-butyl lithium(n-BuLi), in a solvent, e.g., tetrahydrofuran (THF), provides 2-g.Nucleophilic addition of amine 2-h to aryl chloride 2-g using a base,e.g., N,N-diisopropylethylamine (DIPEA), and optionally in a solvent,e.g., N,N-dimethylformamide (DMF), provides the compound of Formula (I).

A mixture of enantiomers, diastereomers, cis/trans isomers resultingfrom the process described above can be separated into their singlecomponents by chiral salt technique, chromatography using normal phase,reverse phase or chiral column, depending on the nature of theseparation.

Biological Assays BTK Kinase Activity Assay

Test inhibitor and controls are prepared in a solvent (i.e., DMSO), andadded to each well of a reaction plate. Full-length active BTK isdiluted in assay buffer and added to each well. After pre-incubation,the kinase reaction is initiated by the addition of an activationmixture diluted in assay buffer containing biotinylated PLCγ2 peptideand ATP. The plates are incubated and the reactions are then stopped inthe dark by the addition of stop/detection mixture prepared in assaybuffer. Assay plates are incubated in the dark, and the plates are readon a plate reader.

BTK C481S Kinase Activity Assay

Test inhibitors and controls are prepared in a solvent (i.e., DMSO) atthe desired final concentration, and added to each well of a reactionplate. Full-length BTKC481S is diluted in assay buffer and added to eachwell in a volume. After pre-incubation, the kinase reaction is initiatedby the addition of an activation mixture diluted in assay buffercontaining biotinylated PLCγ2 peptide, and ATP. The plates are incubatedand the reactions are then stopped in the dark by the addition of astop/detection mixture prepared in assay buffer. Assay plates areincubated in the dark, and the plates are read on a plate reader.

Anti-Proliferation Assay

Cell survival is determined by a MTS assay. Briefly, cells (i.e., TMD-8cells or Rec-1 cells) are plated in a 96-well plate, cultured incomplete growth medium, and then treated with various drugs and drugcombinations. MTS/PMS is added and incubated, followed by assessment ofcell viability using the microplate reader. Data is normalized tountreated controls and analyzed with Microsoft Excel.

Methods of Using the Compounds

Another aspect of the application relates to a method of treating,preventing, inhibiting, or eliminating a disease or disorder associatedwith modulation of BTK (e.g., inhibition of BTK). The method comprisesadministering to a patient in need of a treatment for diseases ordisorders associated with modulation of BTK an effective amount thecompound of Formula (I), or a pharmaceutically acceptable salt,tautomer, prodrug, solvate, metabolite, polymorph, analog or derivativethereof or a pharmaceutical composition of the compound of Formula (I).In one embodiment, the BTK-mediated disorder is selected from immunedisorders, cancer, cardiovascular diseases, viral infections,inflammation, metabolism/endocrine function disorders and neurologicaldisorders. In some embodiments, the method further comprisesadministering an additional therapeutic agent selected from ananti-inflammatory agent, an immunomodulatory agent, chemotherapeuticagent, a neurotropic factor, an agent for treating cardiovasculardisease, an agent for treating liver disease, an anti-viral agent, anagent for treating blood disorders, an agent for treating diabetes, andan agent for treating immunodeficiency disorders. In some embodiments,the BTK is wild-type BTK. In other embodiments, the BTK is mutant BTK(e.g., BTK C481S mutant).

Another aspect of the application relates to a method of treating,preventing, inhibiting, or eliminating a cell proliferative disorder,the method comprising administering to a patient in need thereof atherapeutically effective amount of the compound of Formula (I), or apharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof or a pharmaceuticalcomposition of the compound of Formula (I). In one embodiment, the cellproliferative disorder is a cancer. In some embodiments, the methodfurther comprises administering an additional therapeutic agent selectedfrom an anti-inflammatory agent, an immunomodulatory agent,chemotherapeutic agent, a neurotropic factor, an agent for treatingcardiovascular disease, an agent for treating liver disease, ananti-viral agent, an agent for treating blood disorders, an agent fortreating diabetes, and an agent for treating immunodeficiency disorders.

Another aspect of the application relates to a method of modulating BTK,the method comprising administering to a patient in need thereof atherapeutically effective amount of the compound of Formula (I), or apharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof or a pharmaceuticalcomposition of the compound of Formula (I). In one embodiment,modulating BTK is inhibiting BTK. In some embodiments, the BTK iswild-type BTK. In other embodiments, the BTK is mutant BTK (e.g., BTKC481S mutant).

Another aspect of the application relates to the compound of Formula(I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof, for use in a methodof treating a BTK-mediated disorder. In one embodiment, the disease ordisorder is selected from immune disorders, cancer, cardiovasculardiseases, viral infections, inflammation, metabolism/endocrine functiondisorders and neurological disorders. In some embodiments, the methodfurther comprises administering an additional therapeutic agent selectedfrom an anti-inflammatory agent, an immunomodulatory agent,chemotherapeutic agent, a neurotropic factor, an agent for treatingcardiovascular disease, an agent for treating liver disease, ananti-viral agent, an agent for treating blood disorders, an agent fortreating diabetes, and an agent for treating immunodeficiency disorders.In some embodiments, the BTK is wild-type BTK. In other embodiments, theBTK is mutant BTK (e.g., BTK C481S mutant).

In another aspect, the present application relates to a pharmaceuticalcomposition of the compound of Formula (I), or a pharmaceuticallyacceptable salt, tautomer, prodrug, solvate, metabolite, polymorph,analog or derivative thereof, for use in a method of treating aBTK-mediated disorder. In one embodiment, the disease or disorder isselected from immune disorders, cancer, cardiovascular diseases, viralinfections, inflammation, metabolism/endocrine function disorders andneurological disorders. In some embodiments, the method furthercomprises administering an additional therapeutic agent selected from ananti-inflammatory agent, an immunomodulatory agent, chemotherapeuticagent, a neurotropic factor, an agent for treating cardiovasculardisease, an agent for treating liver disease, an anti-viral agent, anagent for treating blood disorders, an agent for treating diabetes, andan agent for treating immunodeficiency disorders. In some embodiments,the BTK is wild-type BTK. In other embodiments, the BTK is mutant BTK(e.g., BTK C481S mutant).

Another aspect of the application relates to the compound of Formula(I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof, for use in a methodof treating, preventing, inhibiting, or eliminating a cell proliferativedisorder. In one embodiment, the cell proliferative disorder is acancer.

In another aspect, the present application relates to a pharmaceuticalcomposition of the compound of Formula (I), or a pharmaceuticallyacceptable salt, tautomer, prodrug, solvate, metabolite, polymorph,analog or derivative thereof, for use in a method of treating,preventing, inhibiting, or eliminating a cell proliferative disorder. Inone embodiment, the cell proliferative disorder is a cancer.

Another aspect of the application relates to the compound of Formula(I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof, for use inmodulating BTK. In one embodiment, modulating BTK is inhibiting BTK. Insome embodiments, the BTK is wild-type BTK. In other embodiments, theBTK is mutant BTK (e.g., BTK C481S mutant).

In another aspect, the present application relates to a pharmaceuticalcomposition of the compound of Formula (I), or a pharmaceuticallyacceptable salt, tautomer, prodrug, solvate, metabolite, polymorph,analog or derivative thereof, for use in modulating BTK. In oneembodiment, modulating BTK is inhibiting BTK. In some embodiments, theBTK is wild-type BTK. In other embodiments, the BTK is mutant BTK (e.g.,BTK C481S mutant).

Another aspect of the application relates to the use of the compound ofFormula (I), or a pharmaceutically acceptable salt, tautomer, prodrug,solvate, metabolite, polymorph, analog or derivative thereof, in themanufacture of a medicament for treating a BTK-mediated disease ordisorder. In one embodiment, the disease or disorder is selected fromimmune disorders, cancer, cardiovascular diseases, viral infections,inflammation, metabolism/endocrine function disorders and neurologicaldisorders. In some embodiments, the treatment further comprisesadministering an additional therapeutic agent selected from ananti-inflammatory agent, an immunomodulatory agent, chemotherapeuticagent, a neurotropic factor, an agent for treating cardiovasculardisease, an agent for treating liver disease, an anti-viral agent, anagent for treating blood disorders, an agent for treating diabetes, andan agent for treating immunodeficiency disorders. In some embodiments,the BTK is wild-type BTK. In other embodiments, the BTK is mutant BTK(e.g., BTK C481S mutant).

In another aspect, the present application relates to the use of apharmaceutical composition of the compound of Formula (I), or apharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof, in the manufactureof a medicament for treating a BTK-mediated disease or disorder. In oneembodiment, the disease or disorder is selected from immune disorders,cancer, cardiovascular diseases, viral infections inflammation,metabolism/endocrine function disorders and neurological disorders. Insome embodiments, the treatment further comprises administering anadditional therapeutic agent selected from an anti-inflammatory agent,an immunomodulatory agent, chemotherapeutic agent, a neurotropic factor,an agent for treating cardiovascular disease, an agent for treatingliver disease, an anti-viral agent, an agent for treating blooddisorders, an agent for treating diabetes, and an agent for treatingimmunodeficiency disorders. In some embodiments, the BTK is wild-typeBTK. In other embodiments, the BTK is mutant BTK (e.g., BTK C481Smutant).

Another aspect of the application relates to the use of the compound ofFormula (I), or a pharmaceutically acceptable salt, tautomer, prodrug,solvate, metabolite, polymorph, analog or derivative thereof, in themanufacture of a medicament for treating, preventing, inhibiting, oreliminating a cell proliferative disorder. In one embodiment, the cellproliferative disorder is a cancer.

In another aspect, the present application relates to the use of apharmaceutical composition of the compound of Formula (I), or apharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof, in the manufactureof a medicament for treating, preventing, inhibiting, or eliminating acell proliferative disorder. In one embodiment, the cell proliferativedisorder is a cancer.

Another aspect of the application relates to the use of the compound ofFormula (I), or a pharmaceutically acceptable salt, tautomer, prodrug,solvate, metabolite, polymorph, analog or derivative thereof, in themanufacture of a medicament for modulating BTK. In one embodiment,modulating BTK is inhibiting BTK. In some embodiments, the BTK iswild-type BTK. In other embodiments, the BTK is mutant BTK (e.g., BTKC481S mutant).

In another aspect, the present application relates to the use of apharmaceutical composition of the compound of Formula (I), or apharmaceutically acceptable salt, tautomer, prodrug, solvate,metabolite, polymorph, analog or derivative thereof, in the manufactureof a medicament for modulating BTK. In one embodiment, modulating BTK isinhibiting BTK. In some embodiments, the BTK is wild-type BTK. In otherembodiments, the BTK is mutant BTK (e.g., BTK C481S mutant).

In some embodiments of the methods and uses described herein, the canceris selected from breast, ovary, cervix, prostate, testis, genitourinarytract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin,keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma,non-small cell lung carcinoma (NSCLC), small cell carcinoma, lungadenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid,follicular carcinoma, undifferentiated carcinoma, papillary carcinoma,seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma andbiliary passages, kidney carcinoma, pancreatic, myeloid disorders,lymphoma, hairy cells, buccal cavity, naso-pharyngeal, pharynx, lip,tongue, mouth, small intestine, colon-rectum, large intestine, rectum,brain and central nervous system, Hodgkin's leukemia, bronchus, thyroid,liver and intrahepatic bile duct, hepatocellular, gastric,glioma/glioblastoma, endometrial, melanoma, kidney and renal pelvis,urinary bladder, uterine corpus, uterine cervix, multiple myeloma, acutemyelogenous leukemia, chronic myelogenous leukemia, lymphocyticleukemia, chronic lymphoid leukemia (CLL), myeloid leukemia, oral cavityand pharynx, non-Hodgkin lymphoma, melanoma, and villous colon adenoma.

In any of the embodiments of the application, the cancer can be anycancer in any organ, for example, a cancer is selected from the groupconsisting of glioma, thyroid carcinoma, breast carcinoma, small-celllung carcinoma, non-small-cell carcinoma, gastric carcinoma, coloncarcinoma, gastrointestinal stromal carcinoma, pancreatic carcinoma,bile duct carcinoma, CNS carcinoma, ovarian carcinoma, endometrialcarcinoma, prostate carcinoma, renal carcinoma, anaplastic large-celllymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, andcombinations thereof.

In some embodiments of the methods and uses described herein, thedisease or disorder is an immune disorder. In one embodiment, the immunedisorder is rheumatoid arthritis.

In some embodiments of the methods and uses described herein, thedisease or disorder is systemic and local inflammation, arthritis,inflammation related to immune suppression, organ transplant rejection,allergies, ulcerative colitis, Crohn's disease, dermatitis, asthma,systemic lupus erythematosus, Sjogren's Syndrome, multiple sclerosis,scleroderma/systemic sclerosis, idiopathic thrombocytopenic purpura(ITP), anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis, chronicobstructive pulmonary disease (COPD), psoriasis.

In one embodiment, methods of treating a disease or disorder associatedwith modulation of BTK including, immune disorders, cancer,cardiovascular diseases, viral infections, inflammation,metabolism/endocrine function disorders and neurological disorders,comprise administering to a patient suffering from at least one of saiddiseases or disorder the compound of Formula (I).

The disclosed compound of the application can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

The compound of the application can be administered in therapeuticallyeffective amounts in a combinational therapy with one or moretherapeutic agents (pharmaceutical combinations) or modalities, e.g.,non-drug therapies. For example, synergistic effects can occur withother anti-proliferative, anti-cancer, immunomodulatory oranti-inflammatory substances. In some embodiments, the compound ofFormula (I) is administered in combination with an additionaltherapeutic agent selected from an anti-inflammatory agent, animmunomodulatory agent, chemotherapeutic agent, a neurotropic factor, anagent for treating cardiovascular disease, an agent for treating liverdisease, an anti-viral agent, an agent for treating blood disorders, anagent for treating diabetes, and an agent for treating immunodeficiencydisorders. Where the compound of the application is administered inconjunction with other therapies, dosages of the co-administeredcompounds will of course vary depending on the type of co-drug employed,on the specific drug employed, on the condition being treated and soforth.

Combination therapy includes the administration of the subject compoundin further combination with other biologically active ingredients (suchas, but not limited to, an anti-inflammatory agent, an immunomodulatoryagent, chemotherapeutic agent, a neurotropic factor, an agent fortreating cardiovascular disease, an agent for treating liver disease, ananti-viral agent, an agent for treating blood disorders, an agent fortreating diabetes, and an agent for treating immunodeficiency disorders)and non-drug therapies (such as, but not limited to, surgery orradiation treatment). For instance, the compound of the application canbe used in combination with other pharmaceutically active compounds,preferably compounds that are able to enhance the effect of the compoundof the application. The compound of the application can be administeredsimultaneously (as a single preparation or separate preparation) orsequentially to the other drug therapy or treatment modality. Ingeneral, a combination therapy envisions administration of two or moredrugs during a single cycle or course of therapy.

Pharmaceutical Compositions

The present application also provides pharmaceutical compositionscomprising the compound of Formula (I), or a pharmaceutically acceptablesalt, tautomer, prodrug, solvate, metabolite, polymorph, analog orderivative thereof, in combination with at least one pharmaceuticallyacceptable excipient or carrier.

A “pharmaceutical composition” is a formulation containing the compoundof the present application in a form suitable for administration to asubject. In one embodiment, the pharmaceutical composition is in bulk orin unit dosage form. The unit dosage form is any of a variety of forms,including, for example, a capsule, an IV bag, a tablet, a single pump onan aerosol inhaler or a vial. The quantity of active ingredient (e.g., aformulation of the disclosed compound or a pharmaceutically acceptablesalt, tautomer, prodrug, solvate, metabolite, polymorph, analog orderivative thereof thereof) in a unit dose of composition is aneffective amount and is varied according to the particular treatmentinvolved. One skilled in the art will appreciate that it is sometimesnecessary to make routine variations to the dosage depending on the ageand condition of the patient. The dosage will also depend on the routeof administration. A variety of routes are contemplated, including oral,pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous,intramuscular, intraperitoneal, inhalational, buccal, sublingual,intrapleural, intrathecal, intranasal, and the like. Dosage forms forthe topical or transdermal administration of a compound of thisapplication include powders, sprays, ointments, pastes, creams, lotions,gels, solutions, patches and inhalants. In one embodiment, the activecompound is mixed under sterile conditions with a pharmaceuticallyacceptable carrier, and with any preservatives, buffers or propellantsthat are required.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, carriers, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

A pharmaceutical compositions of the application are formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical), andtransmucosal administration. Solutions or suspensions used forparenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfate; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates, and agents for theadjustment of tonicity such as sodium chloride or dextrose. The pH canbe adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

A compound or pharmaceutical composition of the application can beadministered to a subject in many of the well-known methods currentlyused for chemotherapeutic treatment. For example, for treatment ofcancers, a compound of the application may be injected directly intotumors, injected into the blood stream or body cavities or taken orallyor applied through the skin with patches. The dose chosen should besufficient to constitute effective treatment but not as high as to causeunacceptable side effects. The state of the disease condition (e.g.,cancer, precancer, and the like) and the health of the patient shouldpreferably be closely monitored during and for a reasonable period aftertreatment.

The term “therapeutically effective amount”, as used herein, refers toan amount of a pharmaceutical agent to treat, ameliorate, or prevent anidentified disease or condition, or to exhibit a detectable therapeuticor inhibitory effect. The effect can be detected by any assay methodknown in the art. The precise effective amount for a subject will dependupon the subject's body weight, size, and health; the nature and extentof the condition; and the therapeutic or combination of therapeuticsselected for administration. Therapeutically effective amounts for agiven situation can be determined by routine experimentation that iswithin the skill and judgment of the clinician. In one embodiment, thedisease or disorder is selected from immune disorders, cancer,cardiovascular diseases, viral infections, inflammation,metabolism/endocrine function disorders and neurological disorders. Inanother embodiment, the disease or condition to be treated is cancer. Inanother embodiment, the disease or condition to be treated is a cellproliferative disorder.

For any compound, the therapeutically effective amount can be estimatedinitially either in cell culture assays, e.g., of neoplastic cells, orin animal models, usually rats, mice, rabbits, dogs, or pigs. The animalmodel may also be used to determine the appropriate concentration rangeand route of administration. Such information can then be used todetermine useful doses and routes for administration in humans.Therapeutic/prophylactic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., ED₅₀ (the dose therapeutically effective in 50% of thepopulation) and LD₅₀ (the dose lethal to 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceuticalcompositions that exhibit large therapeutic indices are preferred. Thedosage may vary within this range depending upon the dosage formemployed, sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. Factors which maybe taken into account include the severity of the disease state, generalhealth of the subject, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

The pharmaceutical compositions containing active compound (i.e., thecompound of Formula (I)) of the present application may be manufacturedin a manner that is generally known, e.g., by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, or lyophilizing processes. Pharmaceuticalcompositions may be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers comprising excipients and/orauxiliaries that facilitate processing of the active compound intopreparations that can be used pharmaceutically. Of course, theappropriate formulation is dependent upon the route of administrationchosen.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains abasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation are vacuum dryingand freeze-drying that yields a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compound is delivered in the formof an aerosol spray from pressured container or dispenser, whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compound is formulated intoointments, salves, gels, or creams as generally known in the art.

The active compound can be prepared with pharmaceutically acceptablecarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the application are dictated by anddirectly dependent on the unique characteristics of the active compoundand the particular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceuticalcompositions used in accordance with the application vary depending onthe agent, the age, weight, and clinical condition of the recipientpatient, and the experience and judgment of the clinician orpractitioner administering the therapy, among other factors affectingthe selected dosage. Generally, the dose should be sufficient to resultin slowing, and preferably regressing, the growth of the tumors and alsopreferably causing complete regression of the cancer. Dosages can rangefrom about 0.01 mg/kg per day to about 5000 mg/kg per day. An effectiveamount of a pharmaceutical agent is that which provides an objectivelyidentifiable improvement as noted by the clinician or other qualifiedobserver. For example, regression of a tumor in a patient may bemeasured with reference to the diameter of a tumor. Decrease in thediameter of a tumor indicates regression. Regression is also indicatedby failure of tumors to reoccur after treatment has stopped. As usedherein, the term “dosage effective manner” refers to amount of an activecompound to produce the desired biological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the compound of the present application wherein the parent compoundis modified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines, alkalior organic salts of acidic residues such as carboxylic acids, and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include, but are not limitedto, those derived from inorganic and organic acids selected from2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethanedisulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic,glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic,isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic,mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic,pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic,salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic,sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurringamine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

Other examples of pharmaceutically acceptable salts include hexanoicacid, cyclopentane propionic acid, pyruvic acid, malonic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonicacid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, muconic acid, and the like. The present application alsoencompasses salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same salt.

The compound of the present application can also be prepared as esters,for example, pharmaceutically acceptable esters. For example, acarboxylic acid function group in a compound can be converted to itscorresponding ester, e.g., a methyl, ethyl or other ester. Also, analcohol group in a compound can be converted to its corresponding ester,e.g., an acetate, propionate or other ester.

The compound of the present application can also be prepared asprodrugs, for example, pharmaceutically acceptable prodrugs. The terms“pro-drug” and “prodrug” are used interchangeably herein and refer toany compound which releases an active parent drug in vivo. Sinceprodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing,etc.), the compound of the present application can be delivered inprodrug form. Thus, the present application is intended to coverprodrugs of the presently claimed compound, methods of delivering thesame and compositions containing the same. “Prodrugs” are intended toinclude any covalently bonded carriers that release an active parentdrug of the present application in vivo when such prodrug isadministered to a subject. Prodrugs in the present application areprepared by modifying functional groups present in the compound in sucha way that the modifications are cleaved, either in routine manipulationor in vivo, to the parent compound. Prodrugs include the compound of thepresent application wherein a hydroxy, amino, sulfhydryl, carboxy orcarbonyl group is bonded to any group that may be cleaved in vivo toform a free hydroxyl, free amino, free sulfhydryl, free carboxy or freecarbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters (e.g.,acetate, dialkylaminoacetates, formates, phosphates, sulfates andbenzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl)of hydroxy functional groups, esters (e.g., ethyl esters,morpholinoethanol esters) of carboxyl functional groups, N-acylderivatives (e.g., N-acetyl) N-Mannich bases, Schiff bases andenaminones of amino functional groups, oximes, acetals, ketals and enolesters of ketone and aldehyde functional groups in the compound of theapplication, and the like, See Bundegaard, H., Design of Prodrugs,p1-92, Elsevier, N.Y.-Oxford (1985).

The compound, or pharmaceutically acceptable salts, tautomers, prodrugs,solvates, metabolites, polymorphs, analogs or derivatives thereof, areadministered orally, nasally, transdermally, pulmonary, inhalationally,buccally, sublingually, intraperintoneally, subcutaneously,intramuscularly, intravenously, rectally, intrapleurally, intrathecallyand parenterally. In one embodiment, the compound or a pharmaceuticallyacceptable salt, tautomer, prodrug, solvate, metabolite, polymorph,analog or derivative thereof is administered orally. One skilled in theart will recognize the advantages of certain routes of administration.

The dosage regimen utilizing the compound is selected in accordance witha variety of factors including type, species, age, weight, sex andmedical condition of the patient; the severity of the condition to betreated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or pharmaceutically acceptablesalt, tautomer, prodrug, solvate, metabolite, polymorph, analog orderivative thereof employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

Techniques for formulation and administration of the disclosed compoundof the application can be found in Remington: the Science and Practiceof Pharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa. (1995).In an embodiment, the compound described herein, and thepharmaceutically acceptable salts, tautomers, prodrugs, solvates,metabolites, polymorphs, analogs or derivatives thereof, are used inpharmaceutical preparations in combination with a pharmaceuticallyacceptable carrier or diluent. Suitable pharmaceutically acceptablecarriers include inert solid fillers or diluents and sterile aqueous ororganic solutions. The compound or pharmaceutically acceptable salts,prodrugs, solvates, metabolites, polymorphs, analogs or derivativesthereof will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedherein.

All percentages and ratios used herein, unless otherwise indicated, areby weight. Other features and advantages of the present application areapparent from the different examples. The provided examples illustratedifferent components and methodology useful in practicing the presentapplication. The examples do not limit the claimed application. Based onthe present application the skilled artisan can identify and employother components and methodology useful for practicing the presentapplication.

EXAMPLES

The application is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisapplication in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe application is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present application and/orscope of the appended claims.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on either Bruker or Varian spectrometers at 400 MHz.Spectra are given in ppm (δ) and coupling constants, J, are reported inHertz. Tetramethylsilane (TMS) was used as an internal standard. Massspectra were collected using a Waters ZQ Single Quad Mass Spectrometer(ion trap ESI). Purity and low resolution mass spectral data weremeasured using Waters Acquity i-class ultra-performance liquidchromatography (UPLC) system with Acquity Photo Diode Array Detector,Acquity Evaporative Light Scattering Detector (ELSD) and Waters ZQ MassSpectrometer. Data was acquired using Waters MassLynx 4.1 software andpurity characterized by UV wavelength 220 nm, ELSD and ESI. Column:Acquity UPLC BEH C18 1.7 μm 2.1×50 mm; Flow rate 0.6 mL/min; Solvent A(95/5/0.1 10 mM ammonium formate/acetonitrile/formic acid), Solvent B(95/5/0.09 acetonitrile/water/formic acid); gradient: 5-100% B from 0 to2 min, hold 100% B to 2.2 min, then 5% B at 2.21 min.

Abbreviations used in the following examples and elsewhere herein are:

-   DCM dichloromethane-   DIEA N,N-diisopropylethylamine-   DIPEA N,N-diisopropylethylamine-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DTT Dithiothreitol-   EDTA ethylenediaminetetraacetic acid-   EGTA ethylene glycol tetraacetic acid-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   LCMS liquid chromatography-mass spectrometry-   MeOH methanol-   MS mass spectrometry-   NMR nuclear magnetic resonance-   ppm parts per million

Example 1 2-chloro-4-phenoxybenzoate (Intermediate 2-D)

Step 1: 2-chloro-4-phenoxybenzonitrile (Intermediate 2-B)

Phenol (3.66 g, 39 mmol) dissolved in DMF (30 mL) was treated with NaH60% dispersed in oil (1.56 g, 39 mmol) in small portions until gasevolution ceased. The reaction mixture was stirred at room temperaturefor 10 minutes then 2-chloro-4-fluorobenzonitrile (2-A, 5.0 g, 32.5mmol) was added. The mixture was stirred at room temperature for 3 hoursuntil completion (LCMS). The volatiles were removed in vacuo and thecrude product was partitioned in DCM/water. The organic phase wasseparated and washed with a saturated brine solution, dried over Na₂SO₄.Concentration afforded 7.5 g of an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ7.96 (d, J=8.7 Hz, 1H), 7.51 (t, J=7.9 Hz, 2H), 7.33 (d, J=7.4Hz, 1H), 7.30 (d, J=2.3 Hz, 1H), 7.20 (d, J=7.9 Hz, 2H), 7.04 (dd,J=8.7, 2.3 Hz, 1H); MS m/z 230 [M+H]⁺.

Step 2: 2-chloro-4-phenoxybenzoic acid (Intermediate 2-C)

2-chloro-4-phenoxybenzonitrile (2-B, 7.0 g, 30.6 mmol), potassiumhydroxide 5M (100 mL) and EtOH (20 mL) were stirred at reflux for 6hours (until starting material was consumed). The mixture was allowed tocool to room temperature and the mixture was acidified slowly withconcentrated HCl. The precipitate was filtered off and dried, giving abeige solid (2-C, 7.15 g, 94%). NMR (400 MHz, DMSO-d₆) δ13.22 (s, 1H),7.88 (d, J=8.7 Hz, 1H), 7.48 (t, J=7.8 Hz, 2H), 7.27 (t, J=7.4 Hz, 1H),7.16 (d, J=8.0 Hz, 2H), 7.08 (d, J=2.2 Hz, 1H), 6.97 (dd, J=8.7, 2.3 Hz,1H); MS m/z 249 [M+H]₊.

Step 3: methyl 2-chloro-4-phenoxybenzoate (Intermediate 2-D)

2-chloro-4-phenoxybenzoic acid (2-C, 5.0 g, 20.2 mmol)was dissolved inDMF (50 mL) and solid K₂CO₃ (4.15 g, 30.1 mmol) was added. The reactionmixture was cooled to 0° C. and methyl iodide (1.4 mL, 22.2 mmol) wasadded dropwise. The mixture was allowed to warm to room temperature overone hour. The starting material was all consumed within that period. Themixture was diluted with water and extracted with Et2O. Drying andconcentration in vacuo afforded a yellow oil (2-D, 4.15 g, 79%) whichwas used without further purification. NMR (400 MHz, DMSO-d6) δ7.89 (d,J=8.7 Hz, 1H), 7.49 (t, J=7.9 Hz, 2H), 7.29 (t, J=7.4 Hz, 1H), 7.17 (d,J=7.9 Hz, 2H), 7.12 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.7, 2.4 Hz, 1H),3.84 (s, 3H); MS m/z 263 [M+H]⁺.

Example 2(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3]-dlpyrimidin-5-yl)methanone(Compound (I))

Step 1: 5-bromo-4-chloro-7H-pyrrolo[2,3]-dlpyrimidine (Intermediate 2-F)

4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2-E, 20.0 g, 130.7 mmol) dissolvedin DCM (800 mL) was treated portion-wise with N-bromosuccinimide (26.7g, 149.8 mmol), while maintaining the temperature around 25-30° C. Thereaction mixture was stirred at room temperature overnight. Water wasadded (500 mL) and the phases were separated. The organic phase wasdried over Na₂SO₄, filtered and concentrated in vacuo. The crude productwas triturated in Et₂O affording after filtration5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as a white solid (2-F,22.43 g, 74%). M.p.: 242-244° C.; ₁H NMR (400 MHz, DMSO-d₆) δ12.96 (s,1H), 8.61 (s, 1H), 7.94 (s, 1H); MS m/z 232 [M(³⁵Cl, ⁷⁹Br)+H]⁺, 234[M(³⁵Cl, ⁸¹Br)+H]⁺, 234 [M(³⁷Cl, ⁷⁹Br)+H]⁺, 236 [M(³⁷Cl, ⁸¹Br)+H]⁺.

Step 2:(2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(Intermediate 2-G)

To a stirred solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine(2-F, 6.90 g, 29.7 mmol) in THF (200 mL) was added dropwise n-BuLi (2.69M in hexanes, 23.2 mL, 62.3 mmol) at −78° C. under inert atmosphere. Thereaction mixture was kept at −78° C. for one hour and then thepre-cooled (to −78° C.) solution of methyl 2-chloro-4-phenoxybenzoate(2-D, 8.19 g, 31.2 mmol) in THF (80 mL) was added. The reaction mixturewas stirred at −78° C. for one hour then quenched with the addition ofHCl 1N (65 mL). The mixture was allowed to warm to room temperature andwas then extracted with EtOAc (3×100 mL). The combined extracts werewashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Thecrude product was purified by column chromatography (SiO₂,hexanes/EtOAc), giving (2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone as a white solid(2-G, 4.73 g, 41%). ¹H NMR (400 MHz, DMSO-d₆) δ13.426 (s, 1H), 8.75 (s,1H), 8.14 (s, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.49 (t, J=7.9 Hz, 2H), 7.26(t, J=7.4 Hz, 1H), 7.23-7.12 (m, 3H), 7.01 (dd, J=8.5, 2.3 Hz, 1H); MSm/z 384 [M(³⁵Cl, ³⁵Cl)+H]⁺, 386 [M(³⁵Cl, ³⁷Cl)+H]⁺, 388 [M(³⁷Cl,³⁷Cl)+H]⁺.

Step 3:(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone(I)

A mixture of(2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone2-G, 200 mg, 0.52 mmol),((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol (72 mg, 0.54 mmol) andDIPEA (272 μL, 1.56 mmol) was stirred at 160° C. for one hour undermicrowave irradiation. The volatiles were removed in vacuo and theresidue was purified by column chromatography (NH₂—SiO₂, DCM/MeOH),giving(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanoneas an off-white solid ((I), 175 mg, 70%). ¹H NMR (400 MHz, DMSO-d₆)δ12.76 (s, 1H), 8.60 (d, J=7.1 Hz, 1H), 8.25 (s, 1H), 7.64 (s, 1H), 7.58(d, J=8.4 Hz, 1H), 7.48 (t, J=7.6 Hz, 2H), 7.26 (t, J=7.2 Hz, 1H),7.18-7.20 (m, 3H), 7.02 (d, J=8.3 Hz, 1H), 4.67 (s, 1H), 4.16 (d, J=7.7Hz, 2H), 3.49 −3.27 (m, 3H), 3.12 (t, J=11.2 Hz, 1H), 2.19 (d, J=11.4Hz, 1H), 1.78 (d, J=12.9 Hz, 1H), 1.67 −1.49 (m, 1H), 1.39 (d, J=12.3Hz, 1H); MS m/z 479 [M(^(35 Cl)+H]) ₃₀, 481 [M(₃₇Cl)+H]₊.

Example 3 BTK Kinase Activity Assay

Test inhibitor and controls (CGI-1746, GDC-0834, PCI-32765, Dasatinib,and R-406) were prepared in 10% DMSO at 10-fold the desired finalconcentration, and added to each well of a reaction plate (Corning96-well half-area solid white nonbinding surface plate) in a volume of2.5 μl. Full-length active BTK was diluted in assay buffer (50 mM Tris,pH 8.0, 0.02 mg/ml BSA, 10 mM MgCl₂, 1 mM EGTA, 10% glycerol, 0.2 mMNa₃VO₄, 1 mM DTT, 0.1 mM β-glycerophosphate, and 0.2 mM NaF) and addedto each well in a volume of 17.5 μl for a final concentration in the 25μl reaction of 0.08 nM. After a 30 minute pre-incubation at roomtemperature, the kinase reaction was initiated by the addition of 5 μlof an activation mixture diluted in assay buffer containing biotinylatedPLCγ2 peptide and ATP for final concentrations of 150 nM biotinylatedPLCγ2 and 180 μM ATP. The plates were incubated for 60 minutes at roomtemperature. The reactions were stopped in the dark by the addition of10 μl stop/detection mixture prepared in assay buffer containing EDTAand AlphaScreen™ Streptavidin Donor and anti-pTYR100 Acceptor beads. Thefinal concentrations were 10 mM EDTA and 500 ng/well of bothAlphaScreen™ donor and acceptor beads. Assay plates were incubated for60 minutes at room temperature in the dark, and the plates were read ona Perkin Elmer Envision Multilabel plate reader (excitation wavelength:640 nm, emission wavelength: 570 nm). The results are shown in Table 1.

Example 4 BTK C481S Kinase Activity Assay

Test inhibitors and controls (Staurosporine) were prepared in 10% DMSOat 10-fold the desired final concentration, and added to each well of areaction plate (Corning 96-well half-area solid white nonbinding surfaceplate) in a volume of 2.5 μl. Full-length BTKC481S was diluted in assaybuffer (50 mM Tris, pH 8.0, 0.02 mg/ml BSA, 10 mM MgCl₂, 1 mM EGTA, 10%glycerol, 1 mM DTT, 1 mM β-glycerophosphate, and 1 mM NaF) and added toeach well in a volume of 17.5 μl for a final concentration in the 25 μlreaction of 10 nM. After a 30 minute pre-incubation at room temperature,the kinase reaction was initiated by the addition of 5 μl of anactivation mixture diluted in assay buffer containing biotinylated PLCγ2peptide, and ATP for final concentrations of 125 nM biotinylated PLCyγ2,and 60 μM ATP. The plates were incubated for 60 minutes at roomtemperature. The reactions were stopped in the dark by the addition of10 μl stop/detection mixture prepared in assay buffer containing EDTA,Staurosporine and AlphaScreen™ Streptavidin Donor and anti-pTYR100Acceptor beads. The final concentrations were 15 mM EDTA, 1 μMStaurosporine and 500 ng/well of both AlphaScreen™ (AmplifiedLuminescent Proximity Homogeneous Assay) technology donor and acceptorbeads. Assay plates were incubated for 60 minutes at room temperature inthe dark, and the plates were read on a Perkin Elmer Envision Multilabelplate reader (excitation wavelength: 640 nm, emission wavelength: 570nm). The results are shown in Table 1.

Example 5 Anti-Proliferation Assay

Cell survival was determined by the MTS assay. Briefly, cells (i.e.,TMD-8 cells or Rec-1 cells) were plated in a 96-well plate at2,000-10,000 cells per well, cultured for 24 hours in complete growthmedium, and then treated with various drugs and drug combinations for 72hours. MTS/PMS was added and incubated for 4 hour, followed byassessment of cell viability using the microplate reader (absorbance at490 nm). Data were normalized to untreated controls and analyzed withMicrosoft Excel. The results are shown in Table 1.

TABLE 1 Biological activity of Compound (I) BTK (C481S) BTK IC₅₀ (nM)IC₅₀ (nM) MTS/TMD-8 (μM) MTS/Rec-1 (μM) 0.5 ± 0.05 3.0 ± 2.4 0.13 ± 0.060.18 ± 0.07

Equivalents

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

1. A method of treating a BTK-mediated disorder, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, tautomer, prodrug, orsolvate thereof.
 2. The method of claim 1, wherein the BTK-mediateddisorder is selected from immune disorders, cancer, cardiovasculardiseases, viral infections, inflammation, metabolism/endocrine functiondisorders and neurological disorders.
 3. The method of claim 2, whereinthe cancer is selected from breast, ovary, cervix, prostate, testis,genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma,stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cellcarcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma,lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma,thyroid, follicular carcinoma, undifferentiated carcinoma, papillarycarcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, livercarcinoma and biliary passages, kidney carcinoma, pancreatic, myeloiddisorders, lymphoma, hairy cells, buccal cavity, naso-pharyngeal,pharynx, lip, tongue, mouth, small intestine, colon-rectum, largeintestine, rectum, brain and central nervous system, Hodgkin's leukemia,bronchus, thyroid, liver and intrahepatic bile duct, hepatocellular,gastric, glioma/glioblastoma, endometrial, melanoma, kidney and renalpelvis, urinary bladder, uterine corpus, uterine cervix, multiplemyeloma, acute myelogenous leukemia, chronic myelogenous leukemia,lymphocytic leukemia, chronic lymphoid leukemia (CLL), myeloid leukemia,oral cavity and pharynx, non-Hodgkin lymphoma, melanoma, and villouscolon adenoma.
 4. The method of claim 3, wherein the cancer is CLL. 5.The method of claim 2, wherein the disorder is rheumatoid arthritis,systemic and local inflammation, arthritis, inflammation related toimmune suppression, organ transplant rejection, allergies, ulcerativecolitis, Crohn's disease, dermatitis, asthma, systemic lupuserythematosus, Sjogren's Syndrome, multiple sclerosis,scleroderma/systemic sclerosis, idiopathic thrombocytopenic purpura(ITP), anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis, chronicobstructive pulmonary disease (COPD), or psoriasis.
 6. The method ofclaim 1, comprising administering to the patient a therapeuticallyeffective amount of a compound of of Formula (I) or a pharmaceuticallyacceptable salt thereof.
 7. The method of claim 1, comprisingadministering to the patient a therapeutically effective amount of acompound of of Formula (I).
 8. A method of modulating BTK, comprisingadministering to a patient in need thereof an effective amount of acompound of a compound of of Formula (I):

or a pharmaceutically acceptable salt, tautomer, prodrug, or solvatethereof.
 9. The method of claim 8, comprising administering to thepatient a therapeutically effective amount of a compound of of Formula(I) or a pharmaceutically acceptable salt thereof.
 10. The method ofclaim 8, comprising administering to the patient a therapeuticallyeffective amount of a compound of of Formula (I).